ES2334765B1 - IMPROVED PROCESS TO SYNTHEIZE THE FREE BASE OF DEVENLAFAXINE AND SALTS OR SOLVATES OF THE SAME. - Google Patents

Abstract

Improved process to synthesize the free base of desvenlafaxine and salts or solvates thereof. The invention It is generally related to an improved process for synthesize the free base of desvenlafaxine and salts or solvates of the same. The invention also covers powder compositions and dosage forms comprising desvenlafaxine, as well as free base, either in the form of salts or solvates thereof, prepared according to the process of the invention. Finally the invention is also about procedures for preparing a intermediate compound III and the use thereof in the process of synthesis of the desvenlafaxine of the invention.

Description

Improved process to synthesize the free base of desvenlafaxine and salts or solvates thereof.

Field of the Invention

The invention relates, in general, to a Improved process to manufacture desvenlafaxine free base and salts or solvates thereof.

State of the art

Desvenlafaxine (Compound 1, shown at continued) is an active pharmaceutical substance with the formula empirical C 16 H 25 NO 2 and a molecular weight of 263.38. The desvenlafaxine, which can also be called desmethylvenlafaxine and / or O-desmethylvenlafaxine, is the active metabolite Main venlafaxine, an active pharmaceutical ingredient indicated for the treatment of major depressive disorder.

one

U.S. Patent No. 4,535,186 describes the first process to prepare desvenlafaxine. In the U.S. Patent No. 4,535,186, desvenlafaxine is synthesized by the process illustrated in Scheme 1:

       \ vskip1.000000 \ baselineskip
    

Scheme one

       \ vskip1.000000 \ baselineskip
    

2

       \ vskip1.000000 \ baselineskip
    

U.S. Patent No. 5,043,466 describes an improved synthetic process to prepare desvenlafaxine In U.S. Patent No. 5,043,466, it is obtains desvenlafaxine using solvents composed of hydrocarbon as a reaction medium during the reaction of condensation with cyclohexanone. The bibliography describes other alternative processes to prepare desvenlafaxine. Generally, these alternative processes advance through the venlafaxine dimethylation.

       \ vskip1.000000 \ baselineskip
    

Description of the invention

The invention relates, in general, to a Improved process to manufacture desvenlafaxine free base and salts or solvates thereof. In particular, the invention is refers to a synthetic process to prepare desvenlafaxine as illustrated in Scheme 2 shown below. This process Alternative includes preparing desvenlafaxine directly from of its N, N-demethylated derivative (Compound III). In This synthetic process, the dimethylation is advantageously performed without requiring protection of the phenoxy group but adjusting in place the reaction conditions.

Intermediate N, N-Demethylated can be prepared by O-demethylation of the intermediate corresponding to Compound II. The reaction can be carried out. using conventional demethylation conditions, such as the use of sodium hydride with diphenylphosphine, use of dodecanothiol or the use of L-selectride. Then, compound III can N, N-dimethylate by conventional means, by example by reductive methylation by treatment with formaldehyde and formic acid or by treatment with formaldehyde and sodium triacetoxyborohydride.

       \ newpage
    

Scheme 2

       \ vskip1.000000 \ baselineskip
    

3

The compounds represented in Scheme 2, used as starting materials or as intermediates for produce desvenlafaxine, can optionally be used in its form free base or as one of its salts and / or solvates thereof, where appropriate. Similarly, desvenlafaxine obtained according to Scheme 2 it can be isolated in its base form free or as one of its salts or solvates thereof (for example,  desvenlafaxine succinate monohydrate).

Among other things, the invention includes:

Compound (III) obtained in accordance with the process of the invention having a purity of at least about 98%, preferably at least about 99%, and more preferably at least about 99.9%, measured by HPLC.

Desvenlafaxine obtained according to the process of the invention having a purity of at least about 97%, preferably at least about 99%, more preferably at least about 99.8%, measured by HPLC.

Desvenlafaxine succinate obtained from according to the process of the invention having a purity of at less than about 99%, and preferably at least approximately 99.9%, measured by HPLC.

Desvenlafaxine succinate isolated from of desvenlafaxine obtained according to the process of invention that has a particle size distribution where approximately 10% of the total volume (i.e., D 10 (v)) of  the particles have a diameter less than about 4 um, approximately 50% of the total volume (i.e. D 50 (v)) of the particles have a diameter smaller than about 41 µm and about 90% of the volume total (i.e., D 90 (v)) of the particles have a diameter less than about 155 µm.

Desvenlafaxine succinate isolated from of desvenlafaxine obtained according to the process of invention that has a surface area of approximately 0.8457 ± 0.0039 m2 / g.

Reference will now be made in detail to the preferred embodiments of the invention. However, this invention can be shaped in many different ways and should not be considered limited to the embodiments set forth in this document. In addition, and as a specialist in the art will appreciate, The invention can be embodied as a method, system or process.

General Experimental Conditions i. HPLC method

In the examples described below, The following analytical chromatographic HPLC method was used:

Chromatographic separation was performed in a Kromasil 100 C8 column, 5 µm, 25 cm x 4.6 mm. of D.I. to 40 ° C

The mobile phase was prepared by mixing 2,000 g of 0.1 M buffer solution of (NH 4) H 2 PO 4 pH = 6.0 (20:80) and 391.5 g of HPLC grade acetonitrile. The pH of the mixture should be adjusted, if necessary, to 6.4.

A buffer solution of (NH 4) H 2 PO 4 (0.1 M; pH = 6.0) dissolving 28.75 g of (NH 4) H 2 PO 4 in 2,500 g of water and adjusting the pH = 6.0 with H 3 PO 4 or hydroxide of ammonium.

The chromatograph had a 225 detector nm and the flow rate was 1.2 ml per minute at 40 ° C. They prepared test samples (20 µl) dissolving the appropriate amount of sample to obtain a concentration of 1 mg per ml in the phase mobile.

       \ global \ parskip0.970000 \ baselineskip
    

ii. Particle Size Method

The particle size for succinate desvenlafaxine was measured using an analyzer the size of Malvern Mastersizer S particles with an agitated cell for the Small Volume Sample Dispersion Unit MS1. They were used a 300RF mm lens and a 2.4 mm beam length. The samples for the analysis they were prepared by dispersing a heavy amount of desvenlafaxine succinate (approximately 0.1 g) in 20 ml of Lecithin solution, previously prepared by dilution of 1.5 g of Soy Lecithin in 200 ml of Isopar G. Must be mixed gently until the lecithin dissolves (solution of Lecithin). If necessary, the solution can be sonicated. The suspension was supplied dropwise in a measuring cell in the that the previously filled out interference had been corrected with dispersant (Isopar G) until the opacity reached the level wanted. Volume distributions were obtained three times. Before and after analysis, the sample must be purged and washed abundantly the MS1 unit twice with ethanol and at least three times with the dispersant. For characterization, were indicated specifically the values of D 10, D 50 and D 90 (in volume), each being the average of six values available for Each characterization parameter.

       \ vskip1.000000 \ baselineskip
    

iii. Specific Surface Area Method

The specific surface area BET (Brunauer, Emmett and Teller) for desvenlafaxine succinate was measured using a Micromeritics ASAP2010 device. The samples for the analysis were degassed at 30 ° C-70 ° C under vacuum for about two hours. The determination of the absorption of N2 at 77.3ºK for relative pressures in the 0.05-0.3 range for a weighted amount of desvenlafaxine succinate (i.e. approximately 0.5 g).

       \ vskip1.000000 \ baselineskip
    

iv. Residual Solvents (Method and Solutions of Gas chromatography)

Chromatographic separation was performed in a VOCOL capillary column with a film thickness of 3 µm, and 105 m x 0.53 mm ID column The chromatograph had a FID detector and a Head Space injection auxiliary device.

The oven temperature was programmed as Indicate below: Initial, 0-16 minutes to 70 ° C, then the temperature is increased to 150 ° C (speed of increase 25 ° C / minute) and hold at 150 ° C for 3 minutes, then it is increased again to 240 ° C with an increase of 30 ° C per minute. Then, the temperatures of the injector and the detector are adjust to 220 ° C and 250 ° C, respectively. Helium is used as gas carrier at a pressure of 137.89 kPa (20 psi) with a flow of 10 ml / minute and a 5: 1 separation ratio for the Perkin Elmer 8700 and a 3: 1 separation ratio for the Agilent 6890N.

The samples were heated for 30 minutes at 85 ° C in the Head Space device. After heating, the vials were pressurized with helium at 124.10 kPa (18 psi) for 0.3 minutes The sample loop was loaded for 0.15 minutes (volume of the loop = 1 ml) and then injected for 0.5 minutes.

       \ vskip1.000000 \ baselineskip
    

Solutions Acetone stock solution

The acetone stock solution was prepared containing 1010 µg / ml acetone in water diluting a volume known quantitatively of acetone.

Acetone standard solutions

The acetone stock solution was diluted quantitatively with water to obtain solutions containing 0.15, 0.3, 0.5, 1, 2, 4, 10, 25, 51, 63, 101 and 126 µg / ml of acetone.

Test Solutions

The test solutions were prepared by mixing approximately 100 mg desvenlafaxine succinate in 5 ml of Water.

       \ vskip1.000000 \ baselineskip
    

Process

Vials containing samples were closed hermetically with appropriate corrugated caps and analyzed through the Head Space using the conditions described previously.

Specific examples

The following examples are for purposes only. illustrative and are not intended to be, nor should they be considered, a Limitation of the scope of the invention.

       \ global \ parskip1.000000 \ baselineskip
    

Example 1 Preparation of 4- [2-amino-1- (1-hydroxycyclohexyl) ethyl] phenol  using a Selectride Solution

This example illustrates a process to convert Compound II in Compound III according to an aspect of the invention.

A flask of 2 1 at room temperature and in a nitrogen atmosphere was charged with 654 ml (124.33 g, 0.654 mol) of Selectride 1.0 M in THF solution. Then, to the mixture of reaction was added a toluene solution of 29.23 g (156.55 g, 0.117 mol) of 1- [2-amino-1- (4-methoxyphenyl) ethyl] cyclohexanol (ie, Compound II) with stirring at room temperature. Then, tetrahydrofuran was distilled off in an atmosphere of nitrogen between 79ºC and 110ºC. Yellow suspension obtained was heated to reflux (approximately 115 ° C) with stirring continued and remained at this temperature for 2 hours and 30 minutes

Then, the reactor contents were cooled to 10-15 ° C and 300 ml of deionized water was added with continuous agitation. Then, the temperature was adjusted to 20 ° C and stirring was continued for 30 minutes. Then the two phases resulting were acidified with hydrochloric acid (37%) to adjust the pH value to approximately 1.0 ± 0.2 (actual reading 0.99). The mixture was heated to reflux temperature and stirred. at this temperature for 10 minutes. Then the mixture cooled. at room temperature and the phases separated. The aqueous phase is washed twice with 81 ml (70.22 g) of toluene and then with 160 ml of heptane (109.44 g). The aqueous phase obtained was basified with sodium hydroxide with stirring to adjust the pH value between 10.3-10.5.

The resulting white suspension is stirred at room temperature for a minimum of 1 hour. After, the suspension was filtered to give a white solid that dried under vacuum at 60 ° C to produce 24.73 g of 4- [2-amino-1- (1-hydroxycyclohexyl) ethyl] phenol (i.e. Compound III) (Yield: 89.63%; HPLC purity: 98.181%, Test: 92.31%).

       \ vskip1.000000 \ baselineskip
    

Example 2 Preparation of 4- [2-amino-1- (1-hydroxycyclohexyl) ethyl] phenol  using Dodecanothiol

This example illustrates a process to convert Compound II in Compound III according to an aspect of the invention.

A 500 ml multi-mouth flask, equipped with a mechanical stirrer and distillation equipment, it was purged with nitrogen and one, 3 nitrogen atmosphere was maintained. The flask is they added 1- [2-amino-1- (4-methoxyphenyl) ethyl] cyclohexanol (i.e. Compound II) (30 g; 0.115 mol) in toluene, 35.69 ml (0.144 mol) of dodecanothiol and PEG 400. Then, 33.50 were added ml (0.188 mol) of a solution in methanol of sodium methanolate (al 30%) and the reaction mixture was heated to 140 ° C. Methanol and toluene was removed by distillation and the suspension was stirred for 10 hours at 140-150 ° C. Then the temperature was decreased to approximately 45 ° C and 70.8 were added ml of water

Then, 103.3 ml of the suspension was loaded obtained from 155 ml in another reactor together with 28.32 ml of water and 56.64 ml (49.11 g) of toluene. Then, the reaction mixture is stirred for 15 minutes and the resulting aqueous and organic phases They separated. Then, the aqueous phase was washed twice with 37.76 ml.  (32.74 g) of toluene. Then, the pH value of the aqueous phase is adjusted to 2 with aqueous HCl. Subsequently, the aqueous phase acidified was heated at reflux for 10 minutes and left cool to room temperature. A color solution was obtained. yellow (141 ml). Then, 32.25 ml of the solution was loaded into another reactor and the pH value was adjusted to 6-7. Then, 3.5 ml (2.75 g) of 2-propanol and the yellow-orange solution was based on a pH value of 9.5 with 50% sodium hydroxide. The suspension resulting was stirred for about 1 hour at temperature environment to produce a white suspension.

Then, the white suspension was filtered and the solid was washed with 5 ml of water. The resulting wet solid dried under vacuum at 60 until reaching a constant weight to produce 4 g (0.017 mol, 84.75%) of 4- [2-amino-1- (1-hydroxycyclohexyl) ethyl] phenol (i.e. Compound III) (HPLC purity: 98.00%; Test: 96.97%, Ignition Residue: 0.31%).

       \ vskip1.000000 \ baselineskip
    

Example 3 Desvenlafaxine Preparation (o-desmethylvenlafaxine)

This example illustrates a process to convert Compound III in desvenlafaxine (ie, Compound 1) of according to an aspect of the invention.

It was suspended 4- [2-amino-1- (1-hydroxycyclohexyl) ethyl] phenol (i.e. Compound III) (2.12 g; 0.009 mol) in 21.2 ml (16.79 g) of methanol in a nitrogen atmosphere. A suspension was obtained White color. Then, 1.69 ml (0.022 mol) of formaldehyde (37%), followed by 4.46 g (0.021 mol) of sodium triacetoxyborohydride added in portions. The suspension resulting was stirred for 4 hours and 40 minutes at temperature ambient. Then, 21.2 ml of water was added and stirring was added. continued at room temperature for 10 minutes. Methanol is removed by distillation and the resulting solution was washed twice with 10 ml (8.67 g) of toluene. Subsequently, the pH was adjusted to 9.5  with 50% sodium hydroxide. The resulting suspension was cooled to 0-5 ° C and filtered. The wet solid dried at vacuum at 60 ° C until a constant weight is reached to produce 2.11 g (0.008 mol) of desvenlafaxine (HPLC purity: 92.48%; Assay: 114.72%; Yield: 89.0%).

Then, a 1.84 g portion of the obtained devenlafaxine was suspended in 9.2 ml of deionized water and 9.2 ml (7.28 g) of acetone. The suspension was stirred for 30 minutes at room temperature. Then, the suspension was heated to reflux and was maintained at this temperature for 5 minutes. The resulting suspension was cooled to 20-25 ° C and was filter. The wet solid was dried under vacuum at 60 ° C until a constant weight to produce 1.26 g (0.005 mol) of desvenlafaxine (HPLC purity: 97.70%; Test: 100.56%; Yield: 68.5%).

       \ vskip1.000000 \ baselineskip
    

Example 4 Desvenlafaxine Preparation (o-desmethylvenlafaxine)

This example illustrates a process to convert Compound III in desvenlafaxine (ie, Compound 1) of according to an aspect of the invention.

Sodium triacetoxyborohydride was suspended (4.25 g; 0.020 mol) in 10 ml (8.72 g) of isopropyl acetate in one nitrogen atmosphere A white suspension was obtained. Then, a solution of 1.5 ml (0.020 mol) of formaldehyde (37%) with 2.34 g (2 g dry) of 4- [2-amino-1- (1-hydroxycyclohexyl) ethyl] phenol wet (i.e., Compound III) and 10 ml (8.72 g) of isopropyl acetate. The resulting suspension was stirred for 1 Hour at room temperature. Then, 20 ml of water and stirring was continued at room temperature for 10 minutes. Then the resulting organic and accusative phases and the pH value of the aqueous phase was adjusted to 9.5 with sodium hydroxide aqueous. Then 2-propanol (10 ml; 7.85 g) and the resulting suspension was stirred at room temperature during two hours. Then, the suspension was filtered and the solid wet was dried under vacuum at 40 ° C until it reached a constant weight to produce 2.31 g (0.009 mol) of desvenlafaxine (purity according to HPLC: 97.05%; Trial: 122.37%).

Then, a 1.06 g portion of the Desvenlafaxine obtained above was suspended in 6 ml of water deionized Then, the suspension was heated to reflux and was kept at this temperature for one hour. The suspension The resulting was cooled to 20-25 ° C and filtered. He wet solid was dried under vacuum at 40 ° C until it reached a weight constant to produce 0.61 g (0.002 mol) of desvenlafaxine (HPLC purity: 97.44%; Test: 99.15%; Yield: 57.5%).

       \ vskip1.000000 \ baselineskip
    

Example 5 Preparation of 4- [2-amino-1- (hydroxycyclohexyl) ethyl] phenol  using dodecanothiol

This example illustrates a process to convert Compound II in Compound III according to an aspect of the invention.

A suitable reactor and equipment were purged with nitrogen and a nitrogen atmosphere was maintained. Later suspended hydrochloride 1- [2-amino-1- (4-methoxyphenyl) ethyl] cyclohexanol (30 kg; 105 mol) in 90 kg of deionized water. Then the value pH of the resulting solution was adjusted to 13 with hydroxide sodium (50%) and stirred for 30 minutes. Then they were loaded in the reactor 52 kg (60 l) of toluene. Then the mixture of reaction was stirred for 30 minutes and the aqueous and organic phases resulting separated. Subsequently, the aqueous phase was washed with 13 kg (15 l) of toluene. Then the organic extracts  combined were treated with 25.5 kg (30.2 l, 126 mol) of dodecanothiol and 59 kg (52.4 1) of PEG 400. Then, they were added 28.5 kg (29.4 l, 158.3 mol) of a methanolic solution of sodium methanolate (30%) and the reaction mixture was heated to 80 ° C for 1 hour. Subsequently, methanol and toluene are they were distilled off and the suspension was stirred for 12 hours at 140 ± 5 ° C. Then the temperature dropped to approximately 60 ° C and 131 1 of water and 57 kg (65.7 l) were added of toluene. Then, the reaction mixture was stirred for 20 minutes at 45 ± 5 ° C and then the aqueous and organic phases resulting separated. The aqueous phase was washed twice at 45 ± 5 ° C with 65.7 1 (57 kg) and 39.2 l (34 kg) of toluene.

Then n-butanol was charged (30 kg; 37 l) over the aqueous phase and the pH value was adjusted to 9.5-10.0 with sodium hydroxide (50%) at temperature ambient. The resulting suspension was heated to the temperature of reflux and was maintained at this temperature for 30 minutes. The resulting suspension was cooled to 20-25 ° C and was filter. 23.05 kg of 4- [2-amino-1- (hydroxycyclohexyl) ethyl] phenol Wet (Loss on Drying: 2.49%; Yield: 91%; purity according to HPLC: 99.88%; Assay: 99.51%).

23.05 kg of 4- [2-amino-1- (hydroxycyclohexyl) ethyl] phenol  wet in 39 kg (48.1 l) of n-butanol. The suspension was heated to reflux temperature and kept at this temperature for 30 minutes. The resulting suspension is cooled to 20-25 ° C and kept at this temperature for an hour. Then, the suspension was filtered, washed two times with 6 kg of n-butanol and washed with 8 kg of Water. (Loss on drying: 6.63%; Yield: 80.9%; purity according to HPLC: 99.93%; Trial: 101.63%).

       \ vskip1.000000 \ baselineskip
    

Example 6 Desvenlafaxine Preparation (o-desmethylvenlafaxine)

This example illustrates a process to convert Compound III in desvenlafaxine (ie, Compound 1) of according to an aspect of the invention.

21.4 kg (91 mol) of were suspended 4- [2-amino-1- (hydroxycyclohexyl) ethyl] phenol  wet in 87 kg (99.8 l) of isopropyl acetate in one atmosphere of nitrogen The reaction mixture was cooled to 17-22 ° C and 20.6 kg (254 mol) of formaldehyde (37%). The resulting solution was cooled to 0-5 ° C and the aqueous phase separated. Later loaded 3 kg of anhydrous sodium sulfate. In another reactor, it suspended 54 kg (255 mol) of sodium triacetoxyborohydride in 87 kg (99.8 l) of isopropyl acetate at 28 ± 4 ° C. Then the anhydrous solution of isopropyl acetate was added to the suspension of sodium triacetoxyborohydride and the temperature was maintained at 28 ± 4 ° C. Then, the reaction mixture was stirred for 1 hour. at 28 ± 4 ° C.

Then, 100 kg of water in 45 were added minutes Then, the resulting organic and aqueous phases are separated and in the aqueous phase 39 kg (49.7 l) of 2-propanol. The aqueous reaction mixture was cooled to 20-25 ° C and then the pH value was adjusted to 9.5-10.0 with aqueous sodium hydroxide (50%). Then, the suspension was heated to reflux and maintained at this temperature for 30 minutes. The resulting suspension was cooled. at 20-25 ° C and the pH value was checked again and It was corrected with hydrochloric acid (35%). The suspension was stirred at 20-25 ° C and filtered.

Then, 50.10 kg of the wet devenlafaxine obtained (Drying Loss: 13.70%) in 168 kg of deionized water. The suspension was heated to 90-95 ° C and kept at this temperature for 30 minutes The resulting suspension was cooled and maintained at 20-25 ° C for one hour and filtered.

Then, the wet desvenlafaxine obtained (38.2 kg; loss after drying: 21.22%) was suspended at 89 kg (112.4 l) of methanol Then, the suspension was heated to the temperature of reflux and was maintained at this temperature for 30 minutes. The resulting suspension was cooled and maintained at 20-25 ° C for one hour and filtered (Loss on Drying: 0.77%; Yield: 93.20%; HPLC purity: 99.72%; Assay: 100.65%).

21 kg of desvenlafaxine were suspended wet obtained in 71 kg (89.7 l) of methanol. The suspension is heated to reflux temperature and maintained at this temperature for 30 minutes The resulting suspension was cooled to 20-25 ° C, was maintained for one hour at this temperature and filtered. The solid obtained was washed twice with 10 kg of water, (drying loss: 19.93%; yield: 81.81%; HPLC purity: 99.80%; test: 100.16%).

       \ vskip1.000000 \ baselineskip
    

Example 7 Preparation of desvenlafaxine succinate monohydrate

This example illustrates a process to convert desvenlafaxine (i.e., Compound 1) in succinate desvenlafaxine monohydrate according to an aspect of the invention.

Desvenlafaxine (21.30 kg; 80.9 mol) was loaded in a suitable reactor in a nitrogen atmosphere with 9.1 kg (77.06 mol) of succinic acid, 121 kg (153 1) of acetone and 51 kg of water. The suspension was heated to reflux temperature and maintained at this temperature for 30 minutes. The resulting solution is cooled to 50-55 ° C and filtered.

Then, the solution was cooled to 30-35 ° C and held for 3 hours at this temperature. Subsequently, the suspension was cooled to 20-25 ° C and kept at this temperature for 2 hours. Then, the suspension was filtered and washed twice with 6 kg (7.6 l) of acetone. The wet solid (17.8 kg) was dried under vacuum at  60 ± 5 ° C until a constant weight is reached to produce 17.80 kg (44.56 mol) of desvenlafaxine succinate, which was subsequently ground and sieved (HPLC purity: 99.9%; assay: 100.2%; yield: 68.8%).

Desvenlafaxine succinate obtained by processes of the invention typically has the following particle size distribution: D 50 (v): 3.0 to 4.0 \ mum; D 50 (v): from 35.0 to 41.0 µm; D_ {90} (v): 140.0 at 155.0 µm; and typically has the following surface area: 0.8457 ± 0.0039 m2 / g.

Although the invention has been described and illustrated. with a certain degree of particularity, it is understood that the description has been made by way of example only, and that can resort to numerous changes in the conditions and order of stages by specialists in the art without departing of the spirit and scope of the invention.

Claims (54)

1. A process to prepare the free base of the desvenlafaxine and salts or solvates thereof comprising the N, N-dimethylation of 4- [2-amino-1- (hydroxycyclohexyl) ethyl] phenol (Compound III) to obtain the free base of the desvenlafaxine 4 2. The process of claim 1, which it further comprises converting said free base of the desvenlafaxine in salts or solvates thereof. 3. The process of claim 2, wherein said reducing methylation comprises treating Compound III with formaldehyde and sodium triacetoxyborohydride at least in one organic solvent 4. The process of claim 3, wherein said at least one organic solvent is at least one of an alcohol lower, an ester solvent and combinations thereof. 5. The process of claim 3, wherein said at least one organic solvent is at least one of methanol, Isopropyl acetate and combinations thereof. 6. The process of claim 3, wherein said at least one organic solvent is isopropyl acetate. 7. The process of claim 3, which additionally comprises at least one of (i) adding water to the reaction mixture, (ii) extracting the reaction mixture to form at least one organic phase and at least one aqueous phase, (iii) basify the aqueous phase to an appropriate pH value to obtain the desvenlafaxine free base, (iv) isolate the free base from the desvenlafaxine and (v) convert the free base of desvenlafaxine into a salt 8. The process of claim 7, wherein said step of basifying the aqueous phase to an appropriate pH value to obtain desvenlafaxine free base comprises adjusting the pH value between approximately 9.5 and approximately 10.0 with At least one base. 9. The process of claim 8, wherein said at least one base is at least one inorganic base. 10. The process of claim 8, in the that said at least one base is at least one hydroxide base. 11. The process of claim 8, in the that said at least one base is sodium hydroxide. 12. The process of any one of the claims 1 to 11, wherein said free base of desvenlafaxine, and the salts or solvates thereof, have a purity of at least about 97% measured by HPLC. 13. The process of any one of the claims 1 to 11, wherein said free base of desvenlafaxine, and the salts or solvates thereof, have a purity of at least about 99% measured by HPLC. 14. The process of any one of the claims 1 to 11, wherein said free base of desvenlafaxine, and the salts or solvates thereof, have a purity of at least about 99.8% measured by HPLC. 15. The process of any one of the claims 1 to 14, wherein said free base of the desvenlafaxine, and the salts or solvates thereof, is succinate salt  of desvenlafaxine. 16. The process of claim 15, in the that said desvenlafaxine succinate salt is succinate of desvenlafaxine monohydrate. 17. The process of claims 15 and 16, where said process further comprises

i.

treat said free base of desvenlafaxine with succinic acid in acetone and water;

ii.

heat the mixture of stage i. at the temperature of reflux;

iii.

isolate desvenlafaxine succinate salt; Y

iv.

drying said succinate salt of desvenlafaxine

         \ vskip1.000000 \ baselineskip
      

18. The process of any of the claims 15 to 17, wherein said succinate salt of desvenlafaxine has a purity of at least about 99%, measured by HPLC. 19. The process of any of the claims 15 to 17, wherein said succinate salt of desvenlafaxine has a purity of at least about 99.9%, measured by HPLC. 20. The process of claim 17, which further comprising grinding and sieving said succinate salt of desvenlafaxine 21. The process of claim 20, in the that said desvenlafaxine succinate salt has a distribution of particle sizes D 10 (v) of about 4 µm. 22. The process of claim 20, in the that said desvenlafaxine succinate salt has a distribution of particle sizes D 50 (v) of approximately 41 \ mum. 23. The process of claim 20, in the that said desvenlafaxine succinate salt has a distribution of particle sizes D 90 (v) of approximately 155 \ mum. 24. The process of claim 20, in the that said desvenlafaxine succinate salt has a surface area of about 0.8457 ± 0.0039 m2 / g. 25. A process to prepare 4- [2-amino-1- (hydroxycyclohexyl) ethyl] phenol (Compound III) comprising 5

         \ vskip1.000000 \ baselineskip
      

O-demethylation of 1- [2-amino-1- (4-methoxyphenyl) ethyl] cyclohexanol (Compound II) 6

         \ vskip1.000000 \ baselineskip
      

26. The process of claim 25, in the that said O-demethylation comprises treating the Compound II with dodecanothiol. 27. The process of claim 26, in the that said O-demethylation comprises doing react a mixture of Compound II, dodecanothiol and at least one organic solvent in the presence of sodium methanolate. 28. The process of claim 27, in the that said organic solvent is at least one ether solvent. 29. The process of claim 27, in the that said organic solvent is at least one solvent polyether 30. The process of claim 27, in the that said organic solvent is polyethylene glycol. 31. The process of claim 27, which further comprising heating said mixture during about 12 hours at about 140 ° C. 32. The process of claim 27, which additionally comprises at least one of:

i.

add water to said mixture;

ii.

extract said mixture to obtain at least one phase organic and at least one aqueous phase;

ii.

basify said at least one aqueous phase to a value of appropriate pH to obtain Compound III;

iii.

isolate Compound III;

iv.

purify Compound III; Y

v.

Dry Compound III.

         \ vskip1.000000 \ baselineskip
      

33. The process of claim 32, in the that said basification comprises adjusting the pH value between about 9.5 and about 10.0 with at least one base. 34. The process of claim 33, in the that said at least one base is at least one inorganic base. 35. The process of claim 33, in the that said inorganic base is at least one hydroxide base. 36. The process of claim 33, in the that said inorganic base is sodium hydroxide. 37. The process of claim 25, in the that said O-demethylation comprises treating the Compound II with at least one L-selectride. 38. The process of claim 37, in the that said process comprises reacting a mixture of the Compound II and L-selectride in at least one organic solvent 39. The process of claim 38, in the that said organic solvent is at least one non-solvent polar. 40. The process of claim 38, in the that said organic solvent is a hydrocarbon. 41. The process of claim 38, in the that said at least one organic solvent is toluene. 42. The process of claim 37, which further comprising heating said mixture during about 2 hours at about 115 ° C. 43. The process of claim 38, which additionally comprises at least one of:

i.

add water to said reaction mixture;

ii.

extract said mixture to obtain at least one phase organic and at least one aqueous phase;

iii.

basify said aqueous phase to a pH value appropriate to obtain Compound III;

iv.

isolate Compound III;

v.

purify Compound III; Y

saw.

Dry Compound III.

         \ vskip1.000000 \ baselineskip
      

44. The process of claim 43, in the that said basification comprises adjusting the pH value between about 9.5 and about 10.0 with at least one base. 45. The process of claim 44, in the that said base is at least an inorganic base. 46. The process of claim 44, in the that said inorganic base is at least one hydroxide base. 47. The process of claim 44, in the that said inorganic base is sodium hydroxide. 48. The process of any of the claims 25 to 47, wherein said Compound III has a purity of at least about 98% measured by HPLC. 49. The process of any of the claims 25 to 47, wherein said Compound III has a purity of at least about 99% measured by HPLC. 50. The process of any of the claims 25 to 47, wherein said Compound III has a purity of at least about 99.9% measured by HPLC. 51. The process of any of the claims 1-24, wherein said Compound III is prepared by the process of any of the claims 25-50 52. The use of Compound III prepared by the process of any of claims 24-49 in the process of any of the claims 1-24. 53. A powder composition comprising the free base of desvenlafaxine and salts or solvates thereof, wherein said free base of desvenlafaxine, and salts or solvates of the same, they are prepared by the processes of any of the claims 1-24, 51 and 52. 54. A dosage form comprising the free base of desvenlafaxine and salts or solvates thereof wherein said free base of desvenlafaxine, and salts or solvates of the same, they are prepared by the processes of any of the claims 1-24, 51 and 52.